Chronic hepatitis B virus (HBV) infection affects 350 million persons worldwide and approximately 1.5 million Americans. Asian Americans have the highest prevalence of chronic HBV, approximately 10% to 15%, followed by other groups including men who have sex with men, injection drug users, and hemodialysis patients (3% to 5% each). Risk factors for liver failure or hepatocellular carcinoma (HCC) in HBV patients remain undefined, though recent data support virological markers (HBV DMA quantitation) as important. Many questions still remain regarding true factors predictive of disease progression (Significance of intrahepatic cccDNA?) and optimal antiviral treatment strategies defining duration of therapy while minimizing resistance. The objectives and aims of this 7-year study are: 1) to design a database to document HBV natural history, help identify risk factors for disease progression, and establish a well-characterized repository of serum samples and liver tissue for ongoing and future studies; 2) to design a long-term clinical trial to study the resistance profile, efficacy, durability of response, and tolerability of different combinations of nucleos(t)ide analog drugs; and 3) to measure intrahepatic cccDNA decline on the nucleos(t)ide drug combinations. For the database protocol, eAg (+) and eAg (-) chronic HBV patients will be prospectively enrolled into a long-term observational database. Patients will continue to be followed by the investigators per standard-of-care and have demographic data, clinical data, serum/tissue samples, and outcomes data collected at regular time points over the study duration. Antiviral treatment is at the discretion of the individual investigator. The resulting large repository of data and specimen samples will serve as an important resource for future studies. For the clinical trial study, eAg (+) and eAg (-) chronic HBV patients will be randomized 1:1:1 to receive either tenofovir monotherapy, entecavir monotherapy, or tenofovir + entecavir combination therapy for 240 weeks, then observed for relapse. Analyses of phenotypic/genotypic resistance development, rates of eAg seroconversion, HBV DNA undetectability, relapse after therapy, and tolerability will allow comparison of these endpoints between the three treatment strategies. End-of-treatment (Week 240) liver biopsies will allow determination of intrahepatic cccDNA decline for the three treatment strategies when compared to baseline liver biopsies. Information gained from this study will help determine the optimal treatment to prevent resistance + the optimal duration of therapy to achieve durable responses.